This K08 proposal describes a five-year research and training plan that will facilitate the transition of Dr. Sailaja Ghanta to an independent academic researcher in the field of sepsis and cell therapy. Dr. Ghanta has a strong background in basic research and has completed post-graduate training in neonatal-perinatal medicine. Sepsis is a leading cause of morbidity and mortality in intensive care units. Investigations of neonatal septic responses have lagged behind adults. Thus, the candidate's proposal initially focuses on using well-characterized adult models of sepsis and she will transition to independence by translating the knowledge gained from this award to neonatal sepsis. Mesenchymal stromal cells (MSCs), an ideal candidate for a therapeutic, improve survival in murine sepsis by modulating the immune response and producing specialized pro-resolving lipid mediators (SPMs) that promote the resolution of inflammation. MSC efficacy in sepsis may be limited by the oxidative inflammatory microenvironment into which they are administered. As the candidate previously showed, intact autophagy is necessary for MSC survival under oxidative stress. The overarching aim of this proposal is to delineate the role of autophagy in MSCs during sepsis with the long-term goal of modulating autophagy in MSCs to prolong their survival in oxidative environments and optimize MSC therapy for sepsis. The hypothesis that autophagy is necessary for MSC-mediated immunomodulation in sepsis will be tested with the following specific aims: 1. Investigate the importance of the autophagy pathway for the therapeutic effects of MSCs in murine sepsis, 2. Decipher the autophagy dependent effect on the resolution of inflammation by MSCs during sepsis, 3. Determine whether MSCs can improve the outcome of autophagy protein deficient mice during sepsis. This research has significance, as knowledge gained from this study will impact future cell-based therapeutics for the devastating condition of sepsis. Dr. Ghanta will receive mentorship from her scholarship oversight committee composed of distinguished scientists with expertise related to key areas of this proposal including immune responses, autophagy, MSCs, and SPM biology. The training opportunities and resources at Brigham and Women's Hospital (BWH) and Harvard Medical School are an ideal environment for the candidate's career development program. The Department of Pediatric Newborn Medicine at BWH is committed to Dr. Ghanta's success and has assured at least 75% protected time to devote to the activities described in this proposal. The candidate's mentor, Dr. Mark Perrella, is a NIH funded researcher in the field of sepsis and cell therapy. A detailed career development and training plan is presented that includes mentored research, didactic coursework, self-directed readings, seminars, and presentations at scientific meetings. The candidate details a timeline for completion of the research aims, preparation of manuscripts, and a future R01 application. The expertise and knowledge gained from this K08 will enable Dr. Ghanta to obtain R01 funding to launch an independent research career focused on optimizing MSC therapy for neonatal sepsis.
Sepsis, a medical condition caused by an underlying infection, leads to an inflammatory process throughout the body and injury to critical organs. There have been intense efforts to improve the treatment of sepsis, but death rates remain high and the number of people developing sepsis continues to increase. In this project, I will investigate approaches for treating sepsis, using cells (mesenchymal stromal cells, MSCs) as a therapy to eradicate the infection, resolve the inflammatory response, protect organs from injury and improve survival. This project seeks to study the role of autophagy, an alternative pathway to cell death, in MSCs. The long-term goal is to modulate autophagy in order to optimize cell survival in the harsh environments associated with infection, and as a result the therapeutic potential, of MSCs for the devastating disease of sepsis.
| Ghanta, Sailaja; Kwon, Min-Young; Rosas, Ivan O et al. (2018) Mesenchymal Stromal Cell Therapy: Does the Source Matter? Crit Care Med 46:343-345 |
